1. Field
The present invention relates to pharmaceutical combinations, compositions and methods for treating obesity.
2. Description
Bile acids are synthesized in the liver and enter the bile as glycine and taurine conjugates. They are released in salt form in bile during digestion and act as detergents to solubilize and consequently aid in digestion of dietary fats. Following digestion, bile acid salts are mostly reabsorbed in the ileum, complexed with proteins, and returned to the liver through the hepatic portal vein. The small amount of bile acid salts which are not reabsorbed by active transport are excreted via the distal ileum and large intestine as a portion of fecal material. Reducing reabsorption of bile acids within the intestinal tract can lower levels of bile acid circulating in the enterohepatic system thereby potentially reducing emulsification in the upper intestinal tract of dietary fat and reducing intestinal absorption of fat soluble drugs. One method of reducing the amount of bile acids that are reabsorbed, is oral administration of compounds that sequester the bile acids within the intestinal tract and cannot themselves be absorbed.
Orlistat (also known as tetrahydrolipstatin and sold under the brand name XENICAL®) is a potent inhibitor of gastrointestinal lipases, i.e. lipases that are responsible for breaking down ingested fat (gastric lipase, carboxylester lipase, pancreatic lipase). As a consequence of this, unabsorbed fat is excreted in the feces. Pancreatic lipase is the key enzyme for the hydrolysis of dietary triglycerides. Triglycerides that have escaped hydrolysis are not absorbed in the intestine. Pharmacological studies with human patients demonstrate potent inhibition of fat absorption and medically relevant reduction of body weight was achieved using lipase inhibitors. However, in a subgroup of the patients, unpleasant gastrointestinal side effects such as oily spotting, fatty/oily stools, fecal urgency, increased defecation and fecal incontinence are observed. Accordingly, there is a need in the art for lipase inhibiting compositions that minimize or suppress the side effects caused by inhibitors of digestive lipases.